Transcriptional suppression of cytochrome P450 2C11 gene expression by 3-methylcholanthrene

Aromatic hydrocarbon receptor-mediated transcriptional up-regulation of cytochrome P450 (CYP) enzymes of the CYP1A subfamily by polycyclic aromatic hydrocarbons (PAHs) such as 3-methylcholanthrene (MC) is accompanied by down-regulation of rat hepatic CYP2C11 expression at the catalytic activity, protein, and mRNA levels. To gain insight into the molecular mechanism of this CYP2C11 suppression response, we have used a nuclear run-on assay to assess directly the effect of MC on the hepatic transcription rate of the CYP2C11 gene following in vivo administration of MC to adult male rats. A single intraperitoneal dose of MC (40 mg/kg) caused a 179-fold increase in the rate of CYP1A gene transcription at 6 hr, and the rate of CYP2C11 gene transcription was reduced by 51% at this time point, compared with vehicle controls. By 48 hr after MC treatment, the rates of CYP1A and CYP2C11 gene transcription were no longer significantly different from the corresponding vehicle controls. These results indicate for the first time that the suppression of hepatic CYP2C11 caused by in vivo administration of PAHs to adult male rats is at least partially due to a decrease in the rate of transcription of the CYP2C11 gene.